BACKGROUND AND PURPOSE: The purpose of the study was to evaluate the effect of APOE genotype and the feasibility of administering an apolipoprotein E-mimetic therapeutic to modify outcomes in a murine model of intracerebral hemorrhage. METHODS: Intracerebral hemorrhage was induced via stereotactic injection of 0.1 U Clostridial collagenase into the left basal ganglia of wild-type and apolipoprotein-E targeted-replacement mice, consisting of either homozygous 3/3 or 4/4 genotypes. Animals were randomized to receive either vehicle or apolipoprotein E-mimetic peptide. Outcomes included functional neurological tests (21-point neuroseverity score and Rotorod latency) over the initial 7 days after injury, radiographic and histological hemorrhage size at 3 and 7 days, brain water content for cerebral edema at 24 hours, and quantitative polymerase chain reaction for inflammatory markers at 6, 24, and 48 hours. RESULTS: Apolipoprotein-E targeted-replacement mice consisting of homozygous 3/3 demonstrated superior neuroseverity scores and Rotorod latencies over the first 3 days after intracerebral hemorrhage, decreased cerebral edema at 24 hours, and reduced upregulation of IL-6 and endothelial nitric oxide synthase at 6 hours when compared to their apolipoprotein-E targeted-replacement mice consisting of homozygous 4/4 counterparts. After intravenous administration of 1 mg/kg apolipoprotein E-mimetic peptide, both wild-type and apolipoprotein-E targeted-replacement mice consisting of homozygous 4/4 exhibited improved functional outcomes over 7 days after intracerebral hemorrhage, less edema at 24 hours, and reduced upregulation of IL-6 and endothelial nitric oxide synthase when compared to mice that did not receive the peptide. CONCLUSIONS: Our data indicate that APOE genotype influences neurological outcome after intracerebral hemorrhage in a murine model. In particular APOE4 is associated with poor functional outcome and increased cerebral edema. Additionally, this outcome can be modified by the addition of an apolipoprotein E mimetic-peptide, COG1410.
BACKGROUND AND PURPOSE: The purpose of the study was to evaluate the effect of APOE genotype and the feasibility of administering an apolipoprotein E-mimetic therapeutic to modify outcomes in a murine model of intracerebral hemorrhage. METHODS:Intracerebral hemorrhage was induced via stereotactic injection of 0.1 U Clostridial collagenase into the left basal ganglia of wild-type and apolipoprotein-E targeted-replacement mice, consisting of either homozygous 3/3 or 4/4 genotypes. Animals were randomized to receive either vehicle or apolipoprotein E-mimetic peptide. Outcomes included functional neurological tests (21-point neuroseverity score and Rotorod latency) over the initial 7 days after injury, radiographic and histological hemorrhage size at 3 and 7 days, brain water content for cerebral edema at 24 hours, and quantitative polymerase chain reaction for inflammatory markers at 6, 24, and 48 hours. RESULTS:Apolipoprotein-E targeted-replacement mice consisting of homozygous 3/3 demonstrated superior neuroseverity scores and Rotorod latencies over the first 3 days after intracerebral hemorrhage, decreased cerebral edema at 24 hours, and reduced upregulation of IL-6 and endothelial nitric oxide synthase at 6 hours when compared to their apolipoprotein-E targeted-replacement mice consisting of homozygous 4/4 counterparts. After intravenous administration of 1 mg/kg apolipoprotein E-mimetic peptide, both wild-type and apolipoprotein-E targeted-replacement mice consisting of homozygous 4/4 exhibited improved functional outcomes over 7 days after intracerebral hemorrhage, less edema at 24 hours, and reduced upregulation of IL-6 and endothelial nitric oxide synthase when compared to mice that did not receive the peptide. CONCLUSIONS: Our data indicate that APOE genotype influences neurological outcome after intracerebral hemorrhage in a murine model. In particular APOE4 is associated with poor functional outcome and increased cerebral edema. Additionally, this outcome can be modified by the addition of an apolipoprotein E mimetic-peptide, COG1410.
Authors: M J Alberts; C Graffagnino; C McClenny; D DeLong; W Strittmatter; A M Saunders; A D Roses Journal: Lancet Date: 1995-08-26 Impact factor: 79.321
Authors: John R Lynch; Haichen Wang; Brian Mace; Stephen Leinenweber; David S Warner; Ellen R Bennett; Michael P Vitek; Suzanne McKenna; Daniel T Laskowitz Journal: Exp Neurol Date: 2005-03 Impact factor: 5.330
Authors: John R Lynch; Wen Tang; Haichen Wang; Michael P Vitek; Ellen R Bennett; Patrick M Sullivan; David S Warner; Daniel T Laskowitz Journal: J Biol Chem Date: 2003-09-24 Impact factor: 5.157
Authors: Jürg Grünenfelder; Martin Umbehr; Andre Plass; Lukas Bestmann; Friedrich E Maly; Gregor Zünd; Marko Turina Journal: J Thorac Cardiovasc Surg Date: 2004-07 Impact factor: 5.209
Authors: Carol A Colton; Leila K Needham; Candice Brown; Danielle Cook; Karima Rasheed; James R Burke; Warren J Strittmatter; Donald E Schmechel; Michael P Vitek Journal: J Neuroimmunol Date: 2004-02 Impact factor: 3.478
Authors: Daniel T Laskowitz; Beilei Lei; Hana N Dawson; Haichen Wang; Steven T Bellows; Dale J Christensen; Michael P Vitek; Michael L James Journal: Neurocrit Care Date: 2012-04 Impact factor: 3.210
Authors: David L McDonagh; Joseph P Mathew; Willam D White; Barbara Phillips-Bute; Daniel T Laskowitz; Mihai V Podgoreanu; Mark F Newman Journal: Anesthesiology Date: 2010-04 Impact factor: 7.892
Authors: Wei Sun; Amanda Peacock; Jane Becker; Barbara Phillips-Bute; Daniel T Laskowitz; Michael L James Journal: J Clin Neurosci Date: 2012-06-16 Impact factor: 1.961
Authors: Beilei Lei; Huaxin Sheng; Haichen Wang; Christopher D Lascola; David S Warner; Daniel T Laskowitz; Michael L James Journal: J Vis Exp Date: 2014-07-03 Impact factor: 1.355
Authors: Jeffrey T Guptill; Shruti M Raja; Felix Boakye-Agyeman; Robert Noveck; Sarah Ramey; Tian Ming Tu; Daniel T Laskowitz Journal: J Clin Pharmacol Date: 2016-12-19 Impact factor: 3.126